ETIOLOGY OF GLUCOSE INTOLERANCE OF AGING

点击翻译按钮获取中文摘要

Advancing age is characterized by the development of glucose intolerance, leading to increased mortality rates even in the absence of overt diabetes. Along with steady increments in fasting glycemia with age, prolonged elevation in glycemic environment may aid formation of glycated proteins implicated in age-associated complications such as atherosclerosis. The primary objective of this SERCA grant is to identify the factors which contribute to the development of metabolic dysfunction of aging, and to understand the cellular and tissue-specific processes involved in the glucose intolerance of aging. Glucose tolerance is not only determined by insulin secretion and sensitivity, but also by actions of glucose per se, independent of insulin ("glucose effectiveness"), to promote glucose normalization by stimulating transport and uptake of glucose into tissues and by suppressing endogenous production. We propose to quantify glucose effectiveness in young and old rats, and to determine which tissues are responsible for glucose uptake during hyperglycemia alone, with dynamic insulin response suppressed. Given age-associated changes in body composition, we will examine the effect of diet and obesity on glucose effectiveness and determine whether tissue sites of insulin-independent glucose disposal shift with changes in lean body mass. We will examine whether caloric restriction may improve glucose effectiveness and slow development of glucose intolerance, given its ability to extend life span in rodents. We will also explore the extent to which glucose's ability to normalize its own concentration is due to stimulation of glucose transport and cellular uptake versus suppression of endogenous production, and will examine whether the relative contributions are influenced by age. Finally, we will examine the extent to which glucose's stimulation of its own transport, independent of insulin, is mediated by insulin-sensitive glucose transporter isoforms (e.g. GLUT-4) verses transporters which are relatively insensitive to insulin stimulation (e.g. GLUT-1, GLUT-2). Glucose effectiveness will also be quantified in animal models of Type II diabetes, given reports that GLUT-2 protein is defective in diabetes. This candidate has extensively studied the study of biology of non-diseased aging, and has devoted recent years to the investigation of glucose tolerance. She now seeks to combine these two areas, with support of this SERCA, to explore the etiology of age-related glucose intolerance. Her environment at USC provides the strength of metabolic research offered by her sponsor (Dr. Richard Bergman) and strong support and resources in gerontology, in the Andrus Gerontology Center and Dr. Caleb Finch. This candidate is therefore in an excellent position to explore the mechanisms by which glucose intolerance develops with advancing age, in hopes that pathogenesis of age- associated metabolic complications may be averted.